It is known that either the topical application or oral ingestion of certain chemical compounds, known as furocoumarins, certain isomers of which are called psoralens, have an effect on the responsiveness of human skin to sunlight. These psoralen compounds, including 9-methoxypsoralen, which has the generic name of methoxsalen, have long been used in the treatment of certain skin diseases, such as vitiligo, which is characterized by a spotty loss of pigmentation of the skin.
The compound 9-methoxypsoralen having the structural formula ##STR1## and the chemical name 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one has been obtained from natural sources, namely from the fruit of the Ammi Majus Linn. plant, see for example, Fabmu et al., "Ammi Majus Linn. Pharmacognostical study and isolation of crystalline constituent, Ammoidin", Quart. J. Pharm. and Pharmacol., 21:449, 1948.
The present invention is drawn to synthetic processes to produce the compound 9-methoxypsoralen. The following reaction scheme represents the various process steps and novel intermediates which may be utilized to produce methoxsalen (compound of formula I). ##STR2##
II.fwdarw.III
The benzofuranone of the formula II was prepared from 2,6-dihydroxyanisole following procedures set forth by Geissman et al. in Journal of the American Chemical Society, Vol. 73, 5765 (1951). Thereafter the compound of formula II is hydrogenated utilizing hydrogen and a Noble metal such as Palladium on carbon or Platinum in a solvent such as acetic acid. The reaction is carried out at a temperature range of about 15.degree. C. to 50.degree. C. with room temperature preferred. The reaction may be run at atmospheric pressure or under pressures of up to 10 atmospheres with three (3) atmospheres as preferred.
III.fwdarw.IV
The compound of formula III is thereafter reacted (Gattermann reaction) with zinc cyanide and hydrochloric acid at about room temperature to provide a compound of formula IV.
IV.fwdarw.V
The compound of formula IV is thereafter dehydrogenated utilizing dichlorodicyanoquinone in an inert solvent such as dioxane, cyclic ethers such as tetrahydrofuran, or benzene from reflux temperature for the mixture to room temperature with reflux temperature as preferred.
V.fwdarw.VI
The compound of formula V is thereafter reacted with ethyl cyanoacetate to provide the condensed product of formula VI. The reaction is preferably carried out in polar solvent, such as, water and at room temperature.
VI.fwdarw.I
The compound of formula VI is thereafter decarboxylated by heating e.g., above 200.degree. C. in the presence of calcium carbonate.
Yet another variation of the above process sequence involves the following reaction scheme: ##STR3##
V.fwdarw.VII and I
The compound of formula V is reacted with phosphorane of the formula Ph.sub.3 P.dbd.CHCO.sub.2 C.sub.2 H.sub.5 in a Wittig condensation reaction to form the mixture of compounds VII and I. The reaction is carried out in a polar or non-polar inert organic solvent such as methanol, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, high boiling ethers and dimethyl sulfoxide. The reaction temperature ranged from room temperature to reflux, with reflux temperature as preferred.
VII.fwdarw.I
The open compound of formula VII is converted to the closed end product by heating of the open compound under nitrogen, i.e., at a temperature of about 200.degree. C. for at least 30 hours or by photoconversion utilizing methods well known in the art.
It should be noted that intermediate compounds of the formulas III, V, VI and VII are new compounds and as such form a part of the invention since they lead to the useful end product "methoxsalen".